1α,25-Dihydroxyvitamin D3 Potentiates the Beneficial Effects of Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-β

Taher, Yousef A.; Esch, Betty C.A.M. van; Hofman, Gerard A.; Henricks, Paul A.J.; Oosterhout, Antoon J. M. van

doi:10.4049/jimmunol.180.8.5211

Cited by 161 publications

(141 citation statements)

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“…Different previous studies have demonstrated that depletion of IL-10 signaling in a mouse model of IT leads to abrogation of IT-mediated suppression (26,52). In the current study, we could extend these results in a chronic model of allergic airway disease that resembles more closely the human situation when compared with prophylactic models mostly used.…”

Section: Discussionmentioning

confidence: 99%

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IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

Böhm

Maxeiner

Meyer-Martin

et al. 2015

The Journal of Immunology

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Human studies demonstrated that allergen-specific immunotherapy (IT) represents an effective treatment for allergic diseases. IT involves repeated administration of the sensitizing allergen, indicating a crucial contribution of T cells to its medicinal benefit. However, the underlying mechanisms of IT, especially in a chronic disease, are far from being definitive. In the current study, we sought to elucidate the suppressive mechanisms of IT in a mouse model of chronic allergic asthma. OVA-sensitized mice were challenged with OVA or PBS for 4 wk. After development of chronic airway inflammation, mice received OVA-specific IT or placebo alternately to airway challenge for 3 wk. To analyze the T cell–mediated mechanisms underlying IT in vivo, we elaborated the role of T-bet–expressing Th1 cells, T cell–derived IL-10, and Ag-specific thymic as well as peripherally induced Foxp3+ regulatory T (Treg) cells. IT ameliorated airway hyperresponsiveness and airway inflammation in a chronic asthma model. Of note, IT even resulted in a regression of structural changes in the airways following chronic inhaled allergen exposure. Concomitantly, IT induced Th1 cells, Foxp3+, and IL-10–producing Treg cells. Detailed analyses revealed that thymic Treg cells crucially contribute to the effectiveness of IT by promoting IL-10 production in Foxp3-negative T cells. Together with the peripherally induced Ag-specific Foxp3+ Treg cells, thymic Foxp3+ Treg cells orchestrate the curative mechanisms of IT. Taken together, we demonstrate that IT is effective in a chronic allergic disease and dependent on IL-10 and thymic as well as peripherally induced Ag-specific Treg cells.

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Section: Discussionmentioning

confidence: 99%

“…Also, in murine models, IT has shown effects on the development of airway inflammation and airway hyperresponsiveness (AHR) (24)(25)(26)(27). However, in most of the studies, IT was performed prior to first allergen challenge, and the effect of IT on already established airway disease is less well understood.…”

mentioning

confidence: 99%

IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

Böhm

Maxeiner

Meyer-Martin

et al. 2015

The Journal of Immunology

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“…Two broad therapeutic * These authors contributed equally to this work. [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.…”

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confidence: 92%

“…For example, culturing dendritic cells (DCs) with the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α25VitD3) leads to impaired DC maturation, development of tolerogenic properties [3], and the capacity to induce CD4 + Foxp3 + cells with suppressive activity [4], or IL-10 expressing Treg cells [5]. In animal models of human disease, administration of 1α25VitD3 successfully treats transplant rejection [6] and a range of autoimmune conditions, including antiretinal autoimmunity [7], acute colitis [8], diabetes [6], arthritis [9], and EAE [10], as well as allergic airway disease [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.…”

Section: Introductionmentioning

confidence: 99%

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4 + T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3 + regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3 + and IL-10 + CD4 + T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3 + and IL-10 + T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3 + Treg cells over their Foxp3 − T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3 + expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4 + Foxp3 + T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10 + and Foxp3 + Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.Keywords: 1α,25-Dihydroxyvitamin D3 r Asthma r Immune regulation r Regulatory T cells Supporting Information available online IntroductionConsiderable interest exists in the therapeutic potential of regulatory T (Treg) cells to treat a range of immune-mediated patholoCorrespondence: Dr. Catherine M. Hawrylowicz e-mail: catherine.hawrylowicz@kcl.ac.uk gies in humans. This is partly based on evidence obtained from animal models of human disease demonstrating the capacity of Treg cells to control transplant rejection, and to successfully treat autoimmune and allergic disease [1]. Two broad therapeutic * These authors contributed equally to this work. [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4 + IL-10 secreting Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13,14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression in CD3 + CD4 + T cells [12], and restored the impaired steroid-induced IL-10 response in CD4 + cells in vitro [14,15].The present study was designed to further investigate the mechanisms underlying the therapeutic potential of 1α25VitD3 in the context of asthmatic disease, and to determine effects on the induction of both IL-10 + and Foxp3 + T cells. Specifically, we have examined the effects of 1α25VitD3 on total, unfractionated CD4 + T-cell populations, r...

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“…175 Additional types of mucosal adjuvant candidates have been explored, including living parasites, 176 IL-10, TGF-b-inducing compounds 111,177 and natural compounds derived from plants and herbs. 178,179 The collection of data from large, well-designed, double-blind, placebo-controlled, randomized trials with post-treatment follow-up, will provide robust substantiation of current evidence.…”

Section: Resultsmentioning

confidence: 99%

Strategies of mucosal immunotherapy for allergic diseases

Chuang

Chiang

2011

Cell Mol Immunol

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Incidences of allergic disease have recently increased worldwide. Allergen-specific immunotherapy (SIT) has long been a controversial treatment for allergic diseases. Although beneficial effects on clinically relevant outcomes have been demonstrated in clinical trials by subcutaneous immunotherapy (SCIT), there remains a risk of severe and sometimes fatal anaphylaxis. Mucosal immunotherapy is one advantageous choice because of its non-injection routes of administration and lower side-effect profile. This study reviews recent progress in mucosal immunotherapy for allergic diseases. Administration routes, antigen quality and quantity, and adjuvants used are major considerations in this field. Also, direct uses of unique probiotics, or specific cytokines, have been discussed. Furthermore, some researchers have reported new therapeutic ideas that combine two or more strategies. The most important strategy for development of mucosal therapies for allergic diseases is the improvement of antigen formulation, which includes continuous searching for efficient adjuvants, collecting more information about dominant T-cell epitopes of allergens, and having the proper combination of each. In clinics, when compared to other mucosal routes, sublingual immunotherapy (SLIT) is a preferred choice for therapeutic administration, although local and systemic side effects have been reported. Additionally, not every allergen has the same beneficial effect. Further studies are needed to determine the benefits of mucosal immunotherapy for different allergic diseases after comparison of the different administration routes in children and adults. Data collected from large, well-designed, double-blind, placebo-controlled, and randomized trials, with post-treatment follow-up, can provide robust substantiation of current evidence.

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1α,25-Dihydroxyvitamin D3 Potentiates the Beneficial Effects of Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-β

Cited by 161 publications

References 44 publications

IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

Strategies of mucosal immunotherapy for allergic diseases

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1α,25-Dihydroxyvitamin D3 Potentiates the Beneficial Effects of Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-β

Cited by 161 publications

References 44 publications

IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

Strategies of mucosal immunotherapy for allergic diseases

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The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells